A randomized, phase 2 trial of docetaxel with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic head and neck squamous cell cancer.

Abstract

INTRODUCTION:

The phosphotidylinositol-3 kinase (PI3K)/serine-threonine kinase (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is frequently altered in head and neck squamous cell cancer (HNSCC). PX-866 is an oral, irreversible, pan-isoform inhibitor of PI3K. Preclinical models revealed synergy with docetaxel and a phase 1 trial demonstrated tolerability of this combination. This randomized phase 2 study evaluated PX-866 combined with docetaxel in patients with advanced, refractory HNSCC.

METHODS:

Patients with locally advanced, recurrent or metastatic HNSCC who had received at least one and no more than two prior systemic treatment regimens were randomized (1:1) to a combination of docetaxel (75mg/m(2) IV every 21days) with or without PX-866 (8mg PO daily; Arms A and B, respectively). The primary endpoint was progression free survival (PFS). Secondary endpoints included objective response rate (RR), overall survival (OS), toxicity, and correlation of biomarker analyses with efficacy outcomes.

RESULTS:

85 patients were enrolled. There was a non-significant improvement in response rate in the combination arm (14% vs. 5%; P=0.13). Median PFS was 92days in Arm A and 82days in Arm B (P=0.42). There was no difference in OS between the two arms (263 vs. 195days; P=0.62). Grade 3 or higher adverse events were infrequent, but more common in the combination arm with respect to diarrhea (17% vs. 2%), nausea (7% vs. 0%), and febrile neutropenia (21% vs. 5%); grade 3 or higher anemia was more frequent in arm B (7% vs. 27%). PIK3CA mutations or PTEN loss were infrequently observed.

CONCLUSION:

The addition of PX-866 to docetaxel did not improve PFS, RR, or OS in patients with advanced, refractory HNSCC without molecular pre-selection.

• Authors: Antonio Jimeno, Julie E Bauman, Charles Weissman, Douglas Adkins, Ian Schnadig, Patrice Beauregard, Daniel W Bowles, Alexander Spira, Benjamin Levy, Nagashree Seetharamu, Diana Hausman, Luke Walker, Charles M Rudin, Keisuke Shirai
• Journal: Oral oncology (Oral Oncol) Vol. 51 Issue 4 Pg. 383-8 (Apr 2015) ISSN: 1879-0593 [Electronic] England
• PMID: 25593016 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Gonanes
• PX-866
• Phosphoinositide-3 Kinase Inhibitors
• Taxoids
• Docetaxel

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, therapeutic use)
• Carcinoma, Squamous Cell (drug therapy, pathology)
• Docetaxel
• Female
• Gonanes (administration & dosage, pharmacology, therapeutic use)
• Head and Neck Neoplasms (drug therapy, pathology)
• Humans
• Male
• Middle Aged
• Neoplasm Metastasis
• Phosphoinositide-3 Kinase Inhibitors
• Recurrence
• Taxoids (administration & dosage, therapeutic use)